Synthesis of arginine-containing hydroxamate dipeptidomimetics

The syntheses of arginine-containing hydroxamates using various peptide coupling methods are described. Fmoc-Arg(NO₂)-Cl prepared at low temperature did not undergo intramolecular δ-lactam formation and effectively provided desired hydroxamates (8 and 10) in good yields. Fmoc and N-nitro protecting groups can be easily removed. Therefore, this report provides a facile synthesis of arginine-containing peptidomimetic compounds.     

Statistical Mixture Design Applied to RP-HPTLC Chromatographic Separations of Amino Acid Hydroxamates

Abstract

Mixture Design and a Chromatographic Response Function were used to study the effect of different organic solvents as modifiers on the Reversed Phase (C-18) High Performance Thin Layer Chromatographic separation of three amino acid hydroxamates (Arginine hydroxamate, Threonine hydroxamate, and Histidine hydroxamate). Both 3 solvent (methanol, acetonitrile and tetrahydrofuran) and 4 solvent (methanol, acetonitrite, tetrahydrofuran and acetone) systems were studied.     

A novel method for the formation of N-glycosides using hydroxamate

Direct formation of Asn-linked carbohydrate by N-glycosylation has been difficult, because of the lack of nucleophilicity of carboxamide nitrogen. We report here the novel N-glycosylation using Asn hydroxamate as a glycosyl acceptor. Reaction with glycosyl fluoride or glycosyl trichloroacetimidate afforded N-glycoside and subsequent reduction with SmI₂ gave Asn-linked glucose. Carbamate derived hydroxamates proved to have even enhanced reactivity to give N-glycosides in high yields.     

Synthesis of CF3-substituted isoindolones via rhodium(iii)-catalyzed carbenoid C–H functionalization of aryl hydroxamates

An efficient method for the selective preparation of trifluoro-methyl-substituted isoindolones has been developed via Rh^III catalyzed C-H activation / [4 + 1]-annulation of aryl hydroxamates with functionalized acceptor/acceptor diazo compounds as cross-coupling partners.     

The reactivity of Ni(II) toward aspartic and glutamic monohydroxamates

The formation of complexes of Ni(II) with aspartic and glutamic acid hydroxamates was determined by potentiometric methods at I = 0.15 M NaCl and T = 25°C. The equilibrium study of Ni(II) with ASX or GLX revealed that the predominant species formed in solution were (M:L:H⁺): (1:1:0), (1:1:1), (2:1:0), and (2:1:1) in the whole pH range (～3–11). The formation of polymeric species was not observed. The octahedral structures were predicted in which the ligands act as tridentate ligands. The kinetics of complex formation between Ni(II) with ASX system as well as Ni(II) with GLX were also studied in a wide pH range. The observed rate constants for the Ni(II)‐hydroxamates were found to be dependent on the total concentration of hydroxamates at a given pH through the following relations: k_obs = Y₀ + Z(T_ASX) and k_obs = Y₀ + Z(T_GLX) + W(T_GLX)². The trans effect of the hydroxyl group present in the reacting species of Ni(OH)⁺ as well as a ring closure resulted from ligand chelation are introduced as explanations for the rate constants obtained for the reactions of Ni(II) with ASX or GLX. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 38: 540–552, 2006     

Polymer-supported N-derivatized, o-linked hydroxylamine for concurrent solid-phase synthesis of diverse N-alkyl and N-H hydroxamates

We describe parallel/combinatorial, solid-phase, supported synthesis of diverse hydroxamates using a common intermediate, an N-derivatized, O-linked hydroxylamine. The method allows the concurrent synthesis of both N-alkyl and N-H hydroxamates and is compatible with a wide range of chemical transformations. The synthesis of NH hydroxamates includes protection of the nitrogen with a 2,4-dimethoxybenzyl group at the stage of polymer-supported benzyloxyamine. The protecting group eliminates side reactions caused by the presence of a free hydroxamate NH group and is simultaneously removed during cleavage of target compounds from the solid support. The chemical route has been thoroughly tested on model compounds with several linkers, and a high yield and purity synthesis of more than 50 hydroxamates, designed to inhibit cell proliferation of breast cancer cell lines, is described.     

Molecular design and structural optimization of potent peptide hydroxamate inhibitors to selectively target human ADAM metallopeptidase domain 17

Human ADAMs (a disintegrin and metalloproteinases) have been established as an attractive therapeutic target of inflammatory disorders such as inflammatory bowel disease (IBD). The ADAM metallopeptidase domain 17 (ADAM17 or TACE) and its close relative ADAM10 are two of the most important ADAM members that share high conservation in sequence, structure and function, but exhibit subtle difference in regulation of downstream cell signaling events. Here, we described a systematic protocol that combined computational modeling and experimental assay to discover novel peptide hydroxamate derivatives as potent and selective inhibitors for ADAM17 over ADAM10. In the procedure, a virtual combinatorial library of peptide hydroxamate compounds was generated by exploiting intermolecular interactions involved in crystal and modeled structures. The library was examined in detail to identify few promising candidates with both high affinity to ADAM17 and low affinity to ADAM10, which were then tested in vitro with enzyme inhibition assay. Consequently, two peptide hydroxamates Hxm-Phe-Ser-Asn and Hxm-Phe-Arg-Gln were found to exhibit potent inhibition against ADAM17 (K_i = 92 and 47 nM, respectively) and strong selectivity for ADAM17 over ADAM10 (∼7-fold and ∼5-fold, S = 0.86 and 0.71, respectively). The structural basis and energetic property of ADAM17 and ADAM10 interactions with the designed inhibitors were also investigated systematically. It is found that the exquisite network of nonbonded interactions involving the side chains of peptide hydroxamates is primarily responsible for inhibitor selectivity, while the coordination interactions and hydrogen bonds formed by the hydroxamate moiety and backbone of peptide hydroxamates confer high affinity to inhibitor binding.     

Fluorescent Probes Based on Rhodamine Hydrazides and Hydroxamates

Rhodamine hydrazides and hydroxamates derived from hydrazines and hydroxylamines have been applied as fluorescent chemosensors. Reaction‐based irreversible probes based on the specific chemical reactions of reactive target species have been developed and applied in bio‐imaging studies. The strong chelation frames provided by the rhodamine hydrazides and hydroxamates have been utilized for the monitoring of metal ions, amino acids, and reactive acid derivatives. This Personal Account focuses on our perspective of developing fluorescent probes based on rhodamine hydrazides and hydroxamates.

     

Catalyst-Controlled Regiodivergent Synthesis of α/β-Dipeptide Derivatives via N-Allylic Alkylation of O-Alkyl Hydroxamates with MBH Carbonates

A controllable and regiodivergent N-allylation reaction involving readily available O-alkyl hydroxamates derived from natural α-amino acids has been developed, allowing regiospecific access to α/β-dipeptides containing α-unsaturated β-amino acids moieties in moderate to good yields. The regioselectivity could be conveniently switched by alternation of the catalysts and solvents.     

An efficient aerobic oxidation for p -xylene to p -toluic acid catalyzed by cobalt (II) hydroxamates with benzo-15-crown-5

Cobalt (II) hydroxamates with the benzo-15-crown-5 (B15C5) pendant have been synthesized and characterized. These complexes were successfully employed to the oxidation of p-xylene to p-toluic acid with air at 110°C under normal atmospheric pressure. The effects of the B15C5 pendant, the length of chain bonding of B15C5 in these complexes and the addition of alkali metal ions on the oxidation for p-xylene are also investigated by the comparison with the crown-free analogue.     

Dialkylmetallhydroxamate-monomere metallorganische fünfringmoleküle des galliums,indiums und thalliums

The reaction of HON(CH₃)C(O)CH₃ with the trialkyl derivatives of gallium, indium and thallium yields dialkylmetal hydroxamates. The IR-, Raman and ¹H NMR-spectra of these monomeric products with five-membered ringskeletons are discussed. ab]Die Trialkyle des Galliums, Indiums und Thalliums reagieren mit HON(CH₃)C(O)CH₃ unter Bildung von Dialkylmetallhydroxamaten. Die IR-, Raman- und ¹H- NMR-Spektren dieser monomeren Fünfringmoleküle werden diskutiert.     

Synthesis and evaluation of stereopure α-trifluoromethyl-malic hydroxamates as inhibitors of matrix metalloproteinases

The total synthesis of trifluoromethyl (Tfm) analogs of known nanomolar matrix metalloproteinases (MMPs) inhibitors has been performed. The synthetic protocol is based on a moderately stereoselective aldol reaction of trifluoropyruvate with an N-acyl-oxazolidin-2-thione for the construction of the core α-Tfm-malic unit. Both the diastereomeric forms of the target α-Tfm-malic hydroxamates showed micromolar inhibitory potency toward MMP-2 and 9, with a substantial drop with respect to the parent unfluorinated compounds.     

Interaction between aspergillic acid and iron(III): A potentiometric,UV–Vis,H NMR and quantum chemical study

The complex formation equilibria of aspergillic acid with iron(III) were studied by potentiometric and spectrophotometric methods. The ligand was prepared by a biosynthetic route and its purity checked by MS and ¹H NMR spectroscopies. Some structural features of the ligand are discussed on the basis of NMR results. The iron(III) coordination model is compared with those of two other cyclic hydroxamates, 1-hydroxy-2-pyridinone and 1,4-dihydroxy-2-pyridinone, and its features are discussed on the basis of quantum chemical calculations.     

Syntheses and conformations of some cyclic hydroxamates. X-Ray crystal structure of 2-(p-nitrobenzoyl)tetrahydro-2H-1,2-oxazine

Alkylation of potassium p-nitrobenzohydroxamate with 1,4-dibromobutane gave 2-(p-nitrobenzoyl)tetrahydro-2H-1,2-oxazine (3). The X-ray crystal structure of 3 has been determined. The crystals are monoclinic, space group P2₁/n with a = 6.749(1), b = 7.644(1), c = 21.557(2)Å, β = 98.89(1), V = 1098.8(2)ų and Z = 4. The structure, which was refined to R = 0.039 using 1340 observed reflections, shows the oxazine and carbonyl oxygen atoms trans to each other. Alkylation of potassium benzohydroxamate with 1,3-dibromobutane gave a mixture of 3-methyl-2-benzoyloxazolidine (4) and 5-methyl-2-benzoyloxazolidine (5). The ¹H and ¹³C nmr spectra of the mixture of 4 and 5 indicates that these cyclic hydroxamates exist predominantly in the s-trans conformation.     

Solid state conformations of α,β-unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine

α,β-Unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine consistently adopt a defined conformation and undergo highly diastereoselective conjugate addition reactions with lithium amide reagents. The configuration of the N-1-(1′-naphthyl)ethyl group dictates the position of the O-tert-butyl group and also the configuration adopted by the pyramidal nitrogen atom via a ‘chiral relay’ effect. Conjugate addition of lithium amide reagents to these substrates proceeds on the face opposite to both the O-tert-butyl group and nitrogen lone-pair with high levels of diastereoselectivity.     

Chiral Cp‐Rhodium(III)‐Catalyzed Asymmetric Hydroarylations of 1,1‐Disubstituted Alkenes

Metal‐catalyzed functionalizations at the ortho position of a directing group have become an efficient bond‐forming strategy. A wide range of transformations that employ Cp*Rh^III catalysts have been described, but despite their synthetic potential, enantioselective variants that use chiral versions of the Cp* ligand remain scarce (Cp*=pentamethyl cyclopentadienyl). Cyclopentadienyl compounds with an atropchiral biaryl backbone are shown to be suitable ligands for the efficient intramolecular enantioselective hydroarylation of aryl hydroxamates. Dihydrofurans that bear methyl‐substituted quaternary stereocenters are thus obtained by C? H functionalization under mild conditions.     

RhIII-Catalyzed C−H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones

Rh^III-catalyzed C−H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.     

Double asymmetric induction as a mechanistic probe: the doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure α,β-unsaturated esters and enantiopure α,β-unsaturated hydroxamates

The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure α,β-unsaturated esters [derived from Corey’s 8-phenylmenthol chiral auxiliary] and enantiopure α,β-unsaturated hydroxamates [derived from our ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine] has been used as a mechanistic probe to determine the reactive conformations of these acceptors.     

Stereochemically pure α-trifluoromethyl-malic hydroxamates: synthesis and evaluation as inhibitors of matrix metalloproteinases

The synthesis of trifluoromethyl (Tfm) analogs of known nanomolar matrix metalloproteinases (MMPs) inhibitors has been performed. The synthetic protocol is based on a moderately stereoselective aldol reaction of trifluoropyruvate with an N-acyl-oxazolidin-2-thione for the construction of the core α-Tfm-malic unit. Both the diastereomeric forms of the target α-Tfm-malic hydroxamates showed micromolar inhibitory potency toward MMP-2 and 9, according to zymographic tests, with a substantial drop with respect to the parent unfluorinated compounds. We also report some molecular modeling results, which provide a rationale for the experimental findings.